SLAT/Def6 plays a critical role in the development of Th17 cell-mediated experimental autoimmune encephalomyelitis.
SLAT/Def6 plays a critical role in the development of Th17 cell-mediated experimental autoimmune encephalomyelitis.
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DOI：
10.4049/jimmunol.0902573
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Altman A
中科院分区：
文献类型：
--
作者：
Canonigo-Balancio AJ;Fos C;Prod'homme T;Bécart S;Altman A
SWAP-70-like adapter of T cells（SLAT;也称为Def 6）是一种新的Rho GTP酶的鸟嘌呤核苷酸交换因子，先前已显示其在CD 4 + T细胞活化和Th 1/Th 2分化中发挥作用。然而，SLAT/Def 6在自身免疫及其相关的Th 1和Th 17特异性应答中的作用尚未明确阐明。我们使用了一个原型和病理相关的Th 1/Th 17介导的自身免疫模型，即实验性自身免疫性脑脊髓炎，以评估SLAT/Def 6在自身抗原特异性T细胞反应中的作用。我们发现T细胞表达的SLAT/Def 6对于实验性自身免疫性脑脊髓炎的发展和发病机制至关重要，这一点可以通过Def 6缺陷（Def 6 −/−）小鼠对与髓鞘少突胶质细胞糖蛋白免疫的Def 6 −/−小鼠中缺乏CNS炎症和脱髓鞘相关的疾病临床体征的抵抗力得到证明。此外，Def 6缺陷导致髓鞘少突胶质细胞糖蛋白特异性CD 4 + T细胞增殖严重减少，以及次级淋巴器官和CNS中IFN-γ和IL-17产生缺陷。最后，Def 6 −/− CD 4 + T细胞在体外和体内以T细胞内在方式分化为Th 17细胞的能力严重不足。因此，我们的研究建立了T细胞表达的SLAT/Def 6作为Th 17炎症反应的关键正调节因子，因此在控制自身免疫性和炎症性疾病中至关重要。
SWAP-70-like adapter of T cells (SLAT; also known as Def6) is a novel guanine nucleotide exchange factor for Rho GTPases that has been previously shown to play a role in CD4+ T cell activation and Th1/Th2 differentiation. However, the role of SLAT/Def6 in autoimmunity and its associated Th1- and Th17-specific responses has not yet been clearly elucidated. We used a prototypical and pathologically relevant Th1/Th17-mediated autoimmune model, that is, experimental autoimmune encephalomyelitis, to assess the role of SLAT/Def6 in autoantigen-specific T cell response. We found that T cell-expressed SLAT/Def6 was critical for experimental autoimmune encephalomyelitis development and pathogenesis, as evidenced by the resistance of Def6-deficient (Def6−/−) mice to clinical signs of the disease associated with a lack of CNS inflammation and demyelination in myelin oligodendrocyte glycoprotein-immunized Def6−/− mice. Moreover, Def6 deficiency resulted in a severely diminished myelin oligodendrocyte glycoprotein-specific CD4+ T cell proliferation as well as a defect in IFN-γ and IL-17 production in secondary lymphoid organs and the CNS. Lastly, Def6−/− CD4+ T cells were grossly deficient in their ability to differentiate into Th17 cells both in vitro and in vivo in a T cell-intrinsic manner. Therefore, our study establishes T cell-expressed SLAT/Def6 as a pivotal positive regulator of Th17 inflammatory responses and, thus, essential in controlling autoimmune and inflammatory diseases.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.1084/jem.20041538
发表时间：
2005-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Becart, Stephane;Charvet, Celine;Altman, Amnon
通讯作者：
Altman, Amnon
影响因子：
56.9
作者：
KATZ, JD;BENOIST, C;MATHIS, D
通讯作者：
MATHIS, D
DOI：
10.1084/jem.20060244
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chan JR;Blumenschein W;Murphy E;Diveu C;Wiekowski M;Abbondanzo S;Lucian L;Geissler R;Brodie S;Kimball AB;Gorman DM;Smith K;de Waal Malefyt R;Kastelein RA;McClanahan TK;Bowman EP
通讯作者：
Bowman EP